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Summary. Background: Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF-positive microparticles (MPs) may contribute to venous thromboembolism (VTE). Objectives: To conduct a prospective cohort study to determine whether elevated MP-associated TF (MP-TF) activity is predictive of VTE and mortality in four cancer types. Patients/Methods: We determined MP-TF activity in pancreatic, gastric, colorectal and brain cancer patients. We used a chromogenic endpoint assay for all patients and also a chromogenic kinetic assay for patients with pancreatic and brain cancer. Results: During follow-up, 12/60 (20%) pancreatic, 6/43 (14%) gastric, 12/126 (10%) colorectal and 19/119 (16%) brain cancer patients developed VTE; 46/60 (77%), 30/ 43 (70%), 47/126 (37%) and 67/119 (56%), respectively, died. MP-TF activity levels were highest in pancreatic cancer. We did not find a statistically significant association of MP-TF activity with the risk of VTE in any of the four cancer types by using two statistical methods. An association of MP-TF activity with the risk of mortality was detected in pancreatic cancer with the endpoint assay (hazard ratio [HR] 1.8 and 95% confidence interval [CI] 1.4-2.3 per doubling of activity, P < 0.001) and the kinetic assay (HR 1.2, 95% CI 1.1-1.4, P < 0.001); adjustment for type of treatment was not performed. In pancreatic cancer, MP-TF activity correlated with D-dimer level (endpoint assay, r = 0.51; chromogenic assay, r = 0.48), and a correlation between assays (r = 0.61) was found. Conclusion: MP-TF activity was not associated with future VTE in pancreatic, gastric, colorectal and brain cancer. However, we found a strong association of MP-TF activity with mortality in pancreatic cancer. MP-TF activity might be reflective of an aggressive pancreatic cancer phenotype.

Cancer patients are at increased risk of deep vein thrombosis and pulmonary embolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. Biomarkers have been specifically investigated for their capacity of predicting venous thromboembolism (VTE) during the course of disease. Parameters of blood count analysis (elevated leukocyte and platelet count and decreased hemoglobin) have turned out to be useful in risk prediction. Associations between elevated levels and future VTE have been found for d-dimer, prothrombin fragment 1+2, and soluble P-selectin and also for clotting factor VIII and the thrombin generation potential. The results for tissue factor–bearing microparticles are heterogeneous: an association with occurrence of VTE in pancreatic cancer might be present, whereas in other cancer entities, such as glioblastoma, colorectal, or gastric carcinoma, this could not be confirmed. Risk assessment models were developed that include clinical and laboratory markers. In the high-risk categories, patient groups with up to a >20% VTE rate within 6 months can be identified. A further improvement in risk stratification would allow better identification of patients for primary VTE prevention using indirect or novel direct anticoagulants.

Measurement of thrombin generation may help identify patients with cancer at high risk of VTE.

Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis.